Cytoskeleton: Septin wreaths regulate actin in neuritogenesis

Current Biology, Journal Year: 2023, Volume and Issue: 33(3), P. R98 - R100

Published: Feb. 1, 2023

Language: Английский

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Published: Jan. 1, 2024

Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects biological sex age. Risk factors influencing brain development signalling include prenatal inflammation genetic variation. This dissertation aimed build upon these findings by combining behavioural, molecular, neuromorphological investigations mouse models such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) the cytoplasmatic isoforms RNA-binding protein RBFOX1, neuronal deletion small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased for NPDs offspring. While viral-like MIA has been previously established elsewhere, this study was first our institution implement model. I validated NPD-relevant deficits anxiety- depression-like behaviours, as well dose- sex-specific social offspring following early gestation. Proteomic analyses embryonic adult hippocampal (HPC) synaptoneurosomes highlighted novel known targets affected MIA. Analysis dataset implicated neurodevelopmental disruptions lipid, polysaccharide, glycoprotein metabolism, important proper membrane function, signalling, myelination, NPD-pertinent sequelae. In adulthood, observed changes encompassed transmembrane trafficking intracellular apoptosis, cytoskeletal organisation pathways. Importantly, 50 proteins altered HPC were enriched synaptic vesicle cycle. A persistently upregulated cluster formed a functional network involved presynaptic downregulated embryos but adults correlated with deficits. 49/50 genes encoding significantly associated NPD- comorbidity-relevant traits human phenome-wise association data phenotypes. These highlight future intervention at-risk individuals. MIA-evoked neuroarchitecture prefrontal cortex (PFC) male female mice sex- region-specific alterations dendritic spine morphology, possibly underlining behavioural To further investigate NPDs, performed based on implications RBFOX1’s pleiotropic role neuropsychiatric previous preclinical findings. Cytoplasmatic OE which affects stability translation thousands used disseminate its morphology behaviour. RBFOX1 length branching PFC led both HPC. Due ASD-like endophenotypes Rbfox1 KO importance gene × environment susceptibility, probed interaction low-dose Both alone loss perinatal period. Preliminary suggested that might increase anhedonia-like behaviours. Morphological density reduced complexity. post-mortem dorsolateral older did not reveal significant common variant abundance. expand risks, evaluated homo- (KO) or heterozygous (HET) Diras2 novel, DIRAS2’s function is largely unknown, it ADHD humans neurodevelopment vitro. mice, there subtle behaviour, more pronounced males, keeping data. had subtly improved cognitive performance, while HET exhibited behaviours line core symptoms, e.g. earning difficulties (females), response inhibition (males), suggesting dose-sensitivity sex-specificity. The morphological revealed multiple aberrations PFC, HPC, amygdala males. KOs exclusively opposite those HETs NPD-like Region- genotype-specific expression Diras1 six relevant regions females, also revealing differences survival regulator mTOR, underlie differences. conclusion, partial knockdown resembled each other core, NPD-associated phenotypes, full differed from those. My suggest complex sex-dependent relationships between interventions, whose influences converge onto molecular An assessment putative overlap, available proteomic three linked via downstream interactions, upstream regulators. Future studies should distinct shared aspects MIA, DIRAS2

Language: Английский

Pyramidal neuron morphogenesis requires a septin network that stabilizes filopodia and suppresses lamellipodia during neurite initiation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 19, 2022

Summary Pyramidal neurons are the major cell type of forebrain, consisting a pyramidally shaped soma with axonal and apicobasal dendritic processes. It is poorly understood how neuronal morphs from sphere to pyramid, while generating neurites proper shape orientation. Here, we discovered that spherical somata immature neurite-less possess circumferential wreath-like network septin filaments, which promotes myosin II localization suppresses Arp2/3 activity at base filopodial actin bundles. The facilitates neurite formation by stabilizing nascent filopodia, mature neurites, concomitantly maintains consolidated suppressing extension lamellipodia. We show this function critical for morphogenesis spatial orientation pyramidal their in vitro vivo. Therefore, somatic cytoskeleton provides key morphogenetic mechanism neuritogenesis development neurons. Highlights - A controls Septins promote suppress lamellipodial protrusions, respectively scaffold exclude Development requires septins vivo eTOC Radler et al report new neurons, mediated stabilizes filopodia lamellipodia differentially controlling Arp2/3.

Language: Английский